JPS6270317A - Drug preparation containing activated vitamin d3 - Google Patents

Abstract

PURPOSE:To obtain the titled drug preparation resistant to the lowering of titer with time, by compounding an activated vitamin D3 with a specific amount of a natural flavonoid pigment. CONSTITUTION:A drug preparation containing an activated vitamin D3, having antioxidation and photo-stabilization effect and resistant to the lowering of the titer of the activated VD with time can be produced by compounding 1pt.wt. of an activated vitamin D3 (e.g. 1alpha,25-dihydroxycholecalciferol) with >=1pt.wt. of one or more natural flavonoid pigments of formula (R is OH or methoxy) which is a phenolic crystalline substance (e.g. anthocyanidine compound such as shisonin, chalcone compound such as safrole yellow, flavonol compound such as quercetin, flavone compound such as cacao pigment, etc.). EFFECT:The natural flavonoid pigment is oxidized with a peroxide to protect the activated VD and the photo-stabilization activity is effectively exerted by the capability of the pigment to absorb the light having short wavelength.

Description

DETAILED DESCRIPTION OF THE INVENTION [Industrial Application Field 1] The present invention relates to a preparation containing active vitamin D3s used for chronic renal failure, hypoparathyroidism, etc. An active vitamin that successfully suppresses the decrease in the titer of active vitamin D3 over time by blending natural flavonoid pigments into the active vitamin D3 and effectively utilizing its antioxidant and photostabilizing effects. This relates to preparations containing D3.

[Prior art] Active vitamin D3 is affected by hydroxylation at the lα position.
(hereinafter sometimes abbreviated as active VD) is known to exhibit high physiological activity. The physiological effects include (1) 1- an action to promote the absorption of calcium and phosphate in the duodenum;
(2) action of promoting f absorption from bone tissue in cooperation with parathyroid hormone, etc. Therefore, clinically, chronic renal failure and parathyroid II
It holds great promise as a treatment for hypo-I function.

By the way, such active VDs include lα-hydroxycholecalciferol, 24-hydroxycholecalciferol, 25-hydroxycholecalciferol, lα,24-dihydroxycholecalciferol, droxycholecalciferol, 24.25-dihydroxy Cholecalciferol, lα, 24.

Examples include 25-trihydroxycholecalciferol (among them, lα,25-dihy), but all of them are said to be unstable against air, light, heat, etc. +1 + e1 (For childcare, an airtight container is used, and the inside of the container is replaced with nitrogen, argon, etc., and the temperature is +a of -10°C or less. Because it is necessary to do so, Eikatsu M type Vl
) products (this will be explained using soft capsules as an example), the effects of air and light, etc. mentioned above should be taken into consideration.
Various considerations have been made to eliminate this. That is, (A) solvent (for example, ethyl alcohol, medium-chain glycerin fatty acid ester mounds are used, but these solvents block the outside air).
Antioxidants (antioxidants include dibutylhydroxytoluene, propyl gallic acid, propyl gallic acid, sorbic acid, erythorbic acid, and citric acid) are added to the drug solution obtained by dissolving the group r). , 1111 rl acid,
Sterol, phospholipid, d9-α-tocopherol,
- Ascorbic acid and its esters, guaiac butter (9) were blended, and (B) the drug solution had to be filled into soft capsules containing a tar-based pigment to form soft capsules.

Therefore, in the case of 1.4 soft capsules, the formulation 1. In order to avoid the disadvantages of '41I, it is not always possible to fully satisfy the effects of the anti-dilaxation agents and tar-based dyes described in 1-1, and the titer of active M-type VDs may decrease over time. - It was pointed out that Azuma-san would do so. This can basically be said to be the same for liquid preparations of active VDs.

In addition, if the jd of the antioxidant is increased in an attempt to maintain a certain level of stability, an inconvenient problem arises in that it has an adverse effect on the human body.

[Problem to be solved by the invention 1 The present invention has been made in consideration of these 11% circumstances, and the present invention has been developed to provide a 1-
By selecting substances that have excellent effects and have no adverse effects on the human body, and by effectively utilizing these effects, it is possible to reduce active VDs over time without using both antioxidants and tar-based pigments. The purpose of this invention is to provide a preparation containing type 1 vitamin D3 that can significantly suppress the decrease in titer.

To solve problem E/Level L] The uninvented active vitamin D3-containing preparation is active vitamin D3: type 1, flavonoid natural pigment = 1 ton or more! The gist lies in the fact that - is blended.

[Function] The present inventors particularly selected flavonoid natural pigments from among various substances as substances that have both antioxidant and photostabilizing effects and can be applied to pharmaceuticals. The basis for selecting the flavonoid natural pigment is as described below.

The present inventors have based on the fact that ``flavonols, which belong to flavonoid natural pigments, are used in oil-based foods as antioxidants and colorants,'' and have determined the effects of flavonols described in 1-4, particularly as colorants. We came up with the idea that this effect could be applied to medicines in the form of light absorption effect.

By the way, in order to realize this idea, 1- It is necessary that flavonols as coloring agents have the ability to absorb light at short wavelengths (VDs are decomposed by light at short wavelengths). Although this is necessary, the present inventors prepared flavonol solutions with various concentrations in order to clarify this point.
When we examined the light absorption ability on the short wavelength side, we confirmed that it has a light absorption ability that can sufficiently effectively suppress the titer decline over time of VDs in combination with the 1-implantation oxidation effect. did. Antioxidants are also used in oil-based medicines other than VD (e.g. geffanil, copherol, etc.), but these antioxidants (in medicines) also have a light absorption effect on the short wavelength side. This fact also supports the usefulness of the above flavonols.

The mechanism of action of these flavonoid natural pigments is thought to be roughly as follows. The decrease in potency due to oxidation of active VDs is caused by fine peroxides (for example, oxides with -0-0-bonds in the molecule) that are inevitably contained in the solvent of soft capsules. However, if a flavonoid-based natural pigment, color Jj, is added to l'+ in a soft capsule, the flavonoid-based natural pigment will be oxidized by 1.4 peroxides. , As a result, active PI
This is to protect type VDs. For power light stabilization, flavonoid natural pigments have a 1υ wave L (
As a result of the light absorption ability being exhibited effectively, the photolysis is 1111
Controlled 1. ) can be considered.

Here, in the case of d-activation + type 1 vD type and 17, as mentioned above, l
α-Hydroxycholecalciferol, 1α,24-dihydroxycholecalciferol, 1α,25-dihydroxycholecalciferol, 1α,25-dihydroxycholecalciferol Le, 1α, 24.

Examples include 25-1-lihydroxyni11/calciferol, and one or two of these
Insert 1. are selected. These are all representative examples of active P1-type vitamin D3, but in view of the flavonoid natural pigments according to the present invention, it is not necessary to limit it to 1,4 active P1-type vitamin D3. The star may be vitamins such as 1-alpha-hydroxyvitamin D for example 1-alpha-hydroxyvitamin D, which are subject to photolysis.

-Flavonoid natural pigments are extracted from plants and have the following structure: Examples include anthocyanidins such as ethudianin 1, chalcones such as safrole yellow, flavonols such as quercetin and rutin, and flavones such as cacao pigment (flavonols have the strongest effect), and one or more of these 2 insert 1, later is selected.

Next, the formulation of the flavonoid natural pigment will be explained. The present inventors have discovered that flavonoid-based natural pigments! , In order to specify the minimum blending speed that can be achieved for both cases, the active P1 type vr) 9f1:lITf! 11 parts to [7 and 1, flavonoid natural pigments: 0.2 and 0.4.

0, 6, 0.8, 1.0, 1.2
, 1.4 cities), and the antioxidant effect and photostabilizing effect (Table 1) of these drug solutions were investigated. As a result, if you add at least 1.0 parts of flavonoid natural pigment (1 part), 1. No. 1 product I11 will have a 1 part effect
I learned that I can get 7.

IO Naka 1 +: Meng Since tll, which is separately defined as the early stage, is specified as ), (), it is preferable to specify (l(). ] 0. It is preferable to use it as a liquid preparation depending on the taste), and regarding the dissolution of live individual VDs (whether to form an oil P1 solution or an emulsifiable solution, etc.) and concentration, etc. It is preferable that the drug be prescribed in consideration of formulation conditions, clinical conditions, etc.

As an example, the production method for producing an oily solution and an emulsifiable solution will be described below.

(a) When preparing an oily solution: Dissolve activated VD in alcohol, and add medium-chain glycerin fatty acid esters, refined vegetable oils such as corn oil, olive oil, K (J oil, etc.), triglycerides, monoglycerides, etc., and if necessary. It is appropriate to add glycerin, propylene glycol, etc. for dissolution.

(b) When making a single solution for emulsification: Dissolve active type VI I) in alcohol, then add gum arabic, hard fat, polyethylene glycol, monoglyceride, triglyceride polyhydric alcohol, glycerin fatty acid ester, cacao butter, as necessary. In that case, it is appropriate to dissolve it by adding glycerin, propylene glycol, etc. Judging from the viewpoint of such dissolution mode, it was found to be 40,000 in the -1- limit of flavonoid-based natural pigments.

Soft capsules contain the thus obtained active VD oil +
It is manufactured by adding a flavonoid natural pigment dissolved in ethyl alcohol, propylene glycol, etc. to a solution or emulsifying solution, stirring and dissolving it, and then filling it into soft capsules.

The above-mentioned emulsifying solution is generally solid at room temperature (liquid at temperatures below 45°C), so capsules filled with it are prepared by mixing one solution in oil. It was found that the antioxidant effect was significantly higher than that of the same type.

[Example] Example 1 97 g of medium-chain glycerin fatty acid, 0.5 mg of lα-hydroxycholecalciferol, and quercetin Ig were dissolved in 5 mJ1 of ethyl alcohol under a nitrogen gas stream.
This was used as a soft capsule filling liquid and was filled into soft capsule shells (made of gelatin and glycerin) according to a conventional method to obtain soft capsules. Contents of capsule F and l are 100+
sg, of which lα-hydroxycholecalciferol was 0.5 g.

Example 2 0.5 g of 1α-hydroxycholecalciferol, 0.5 g of quercetin Ig) JI and shisonin were dissolved in ethyl alcohol io+nJ1 under a nitrogen gas atmosphere of -'F, and 35 g of hard fat and triglyceride were dissolved therein. 30 g of glycerin fatty acid ester, and 5.5 g of polyethylene glycol (polymerization 1f = 1500) were heated in a 45°C water bath to prepare a capsule filling liquid. lα-Hydroxylo 1 was filled in an orange hard capsule made of gelatin and glycerin according to a conventional method with a single capsule content of 1100 mg, and after the contents solidified, the boundary between the capsule head and body was covered with a gelatin film. /calciferol 0-
Hard capsules containing a total of 5 p-g were obtained.

Note that Example 1.2 is summarized in Table 2.

In particular, in order to test the antioxidant effect and photostabilizing effect of the soft capsule obtained in Example 1, the inventors of the Wood Invention Company prepared lα-hydroxylated/calcium chloride containing no flavone-ide natural pigments. As a ferol soft capsule and an antioxidant,
1α-hydroxycholecalciferol soft capsules containing dibutylhydroxytoluene (0.3Φ1-%) were prepared in fl from 1. Comparative test with the described capsule i=1
Shita. For this inspection/l, (1) 40'C17
5% RH (relative humidity 1 L), 6 months, (2) 2000 lux diffused light, 3 months harsh test conducted, experiment started 11ν
The residual rate was determined as 100%, and the results are summarized in Tables 3 and 4. The residual rate was determined using high performance oil body chromatography.

Table 3 Table 4 [Effects of the invention] The present invention is as follows. Because it is composed of It was possible to significantly and safely suppress the decrease in titer, thereby providing a safe and stable active vitamin D3-containing preparation that can withstand long-term storage for 1 minute.

Claims (1)

[Claims] An active vitamin D_3-containing preparation characterized by blending 1 part by weight of active vitamin D_3 with 1 part by weight or more of a flavonoid natural pigment.